HIV is most often transmitted by sexual contact and women are more likely to be infected than men. Thus, there is an urgent need for the development of prevention methods, such as topical microbicides, that put the power of use in the hands of women. Additionally, it is essential that any effective AIDS vaccine protects women, as well as men, from infection. Given the significant challenges that lie ahead for the development of these prevention strategies, the combined use of topical microbicides and vaccines to immunologically contain the lowered viral challenge early holds promise that warrants investigation. Because of the similarities existing between humans and rhesus macaques (RM) at the physiological and immunological levels, infection of these non-human primates with SIV or SHIV represents reasonable models to study HIV transmission and for the evaluation of candidate intervention strategies. Accordingly, we propose to use SHIV infection of RM to test the following hypothesis: there is synergy between vaccination and topical microbicides in conferring protection against infection with CCR5 (RS)-using viruses that represent the majority of sexually transmitted cases. We will test this hypothesis by addressing the following two Specific Aims: (SA1) Evaluate the efficacy of a DNA prime/Ad5 boost vaccination protocol in RM against infection with R5 SHIV using a repeated low-dose challenge model that more closely mimics the dynamics of natural HIV transmission. (SA2) Determine whether topical application of a candidate microbicide, e.g. cellulose acetate 1,2-benzenedicarboxylate (CAP), prior to each challenge in the vaccinated macaques confers added protection. We believe that information gained from the proposed studies will be invaluable for the design, testing and interpretation of preventive strategies against HIV infection in women.